Anti-bspkessiye n-morpholine-beta-
ethylhybsazine



United States Patent fiice.

3,172,8lh Patented Mar. 9, i965 3,1723% ANTl-DEPREEeSlVE N-MORPHGLWE-BETA- ETHYLHYDRAZENE Alfred Halpern, Great Neelr, N.Y., assignor to Synergistics, inc, New Yorlr, NY, a corporation of New York No Drawing. Filed Aug. 9, 1962, Ser. No. 215,777 8 Claims. (tCl. l6'7-e5) This invention relates to new pharmaceutical preparations of heterocyclic alkyl hydrazines and their use in the method of treating disease states relating to the monamine oxydase enzyme system. In particular, this invention is concerned with pharmaceutical preparations comprising N-morpholine-beta-ethyl-hydrazine and its acid addition v salts and the use of the said preparations in the method of treating pathologic states which are affected by the monamine oxydase enzyme system.

This application is a continuation-in-part of applicants co-pending application Serial No. 61,830, filed October 11, 1960, now United States Patent No. 3,Q86,975.

The study of the metabolism of the physiologic stressor amines (epinephrine, norephinephrine and serotonin) has shown that these substances are substrates for the monamine oxydase enzyme system. These stressor amines appear to be implicated in central nervous system and autonomic nervous system activity as well as cardiac function and to exert pronounced vascular actions and other physiologic responses.

Both monamine oxydase and its substrate are found in high levels in the hypothalamus, and it has been suggested that the amine substrate compounds play an important role in neurotransmission somewhat similar to acetylcholine. It has been postulated that certain malfunctioning of the central nervous system is due to the depletion of the neurohumoral agents by their too rapid destruction by the monamine oxydase system. Thus, for example, the therapy for true depressions has been previously limited to the replacement of these amines by the administration of central nervous system acting amine compounds (sympathomimetic amines) for the milder cases, although electroconvulsive shock therapy has been required in addition for the severe depressions when suicidal tendencies were evident.

More recently, the new therapeutic approach has been suggested which proposes to inhibit the enzymatic destruction of these stressor amines through the administration of specific chemical compounds which block the enzyme system. This blockade of the monamine oxydase system has afforded a new therapeutic horizon, offering new hope to those patients suffering from diseases caused by an imbalance of the enzyme-substrate levels, through a biochemical-physiologic approach.

There are several groups of compounds which have been shown to selectively inhibit the enzymatic action of monamine oxydase enzyme in vivo. These may be separated into two classes of compounds according to their duration of action. Those compounds exhibiting a long duration of action consist mainly of the hydrazine derivatives, and those compounds exhibiting a short duration of action consist of the Harmala alkaloids and others of differing chemical structures (such as amphetamine).

Although, for therapeutic reasons, the long-acting class of monamine oxydase inhibitors have been preferred ones, these compounds have been shown to cause serious sidereactions ranging from mild local tissue responses to death. The more commonly encountered side effects in the clinical usage of the hydrazine type of monamine oxidase inhibitors have been hypotension, anemia and liver damage. Members of the short-acting group have also been reported to cause untoward reactions which limit their therapeutic use. The need for a safe, effective means to restore the physiologic neurohumoral balance has been noted many times.

it is important to note that virtually all of the monamine oxdase inhibitor compounds are patterned after the structure of epinephrine (excepting the Harmala alkaloids). These compounds contain an unsaturated cyclic nucleus and an alkyl side-chain of from 2 to 4 carbons, which is substituted in the beta-position by bydrazine. This structural relationship has given rise to a postulated mechanism of activity which describes these hydrazine derivatives as pseudo-amines acting to replace the physiologically active neurohurnoral amines as an enzyme substrate. Although this mechanism of action has not been universally accepted, other investigators have confirmed the close similarity between the physiologic behavior of the amine oxydase inhibitor compounds and the naturally occurring amine enzyme substrate.

The subject compounds of the present invention, although hydrazine derivatives, are not related to physiologically occurring stressor amine compounds and do not possess the noxious side reactions which have been described for other hydrazine derivatives, and yet are potent amine-oxidase inhibitors. The subject compounds of the present invention are heterocyclic derivatives comprising the heterocyclic nucleus of'morpholine to which is attached an ethyl side-chain through the nitrogen atom of the morpholine ring as well as a hydrazine group.

N-morpholine-beta-ethyl hydrazine may be prepared through the reaction between hydrazine and N-morpholine-beta-ethyl chloride in alcoholic media. The compound is obtained as an oil which may be converted to a solid crystalline form by reaction with both pharmaceutically acceptable inorganic and organic acids. The hydrochloric acid salt of N-morpholine-beta-ethyl hydrazine is soluble in water, methanol and chloroform, but is insoluble in ether, benzene and acetone. The acid salts are stable and may be utilized in preparations of pharmaceutical dose forms for therapeutic use.

When it is desired to utilize N-morpholine-beta-ethyl hydrazine or its salts in therapy, it may be administered in the form of a tablet, capsule, granule or suppository in a dosage range from 1.0 to mg. per day, administered in divided doses. For initial treatment, the preferred dosage is 30 to 50 mg. per day, administered in divided doses of 10 mg. each, and if more is required, an additional 20 mg. may be administered at bedtime. Improvernent should be seen within one week. After maximum benefit is attained, the dosage may be slowly reduced over a period of several weeks until a maintenance level is achieved. This maintenance level may range from 1 to 30 mg. per day, although it is preferred that the maintenance dosage be established by determining the individual requirements of the patient.

Tablets of l -morpholine-beta-ethyl hydrazine and its salts are prepared by mixing with a pharmaceutically suitable diluent, as for example, mannitol, lactose, starch or sucrose and a lubricant such as stearic acid or magnesium stearate. The size of the tablet may range from inch in diameter to /8 inch in diameter, although the preferred tablet size is Vs inch in diameter. The usual ratio of the diluent to the lubricant is 50 parts diluent for each part lubricant and the range in concentration of the active ingredient in these tablets may vary from 1 mg. to 75 mg, although 10 mg. to 25 mg. is the preferred range of concentration. The usual ratio of diluent to active ingredient is from equal parts of diluent and active ingredient to 10 parts of diluent for each part of active ingredient. When the tablets are prepared, the active ingredient is intimately mixed with the diluent and the lubricant added. The mixture is granulated through a No. 60 mesh screen, utilizing a granulating solution, as for example, 50 percent alcohol-water, 1 percent gelatin solution or l percent gum arabic solution. The granulated mass is then dried and compressed into the proper tablet size and shape.

Capsules are prepared by either filling a simple mixture of equal parts of active ingredient and a pharmaceutically suitable diluent, as for example, mannitol, lactose and sucrose, in a suitable hard gelatin capsule. Under certain conditions, it may be desired to dissolve the active ingredient in an inert liquid substance, as for example, cottonseed oil, and to utilize this solution to prepare liquid-filled, soft gelatin capsules. When a solid capsule s desired, the use of a lubricant may be indicated to permit rapid, automatic machine-filling or" the capsules, but this is not necessary to the manufacturing procedure when smaller lots are prepared.

The concentration of active ingredient in each capsule may range from 1 mg. to 75 mg. for either the solid-filled capsule or the liquid-filled capsule. It should be noted that when the lower unit dosage of acti e ingredient, as for example, between 1 mg. to 38' mg. of active ingredient is used, then larger quantities of diluent would be required for proper capsulation. In these instances, the ratio of active ingredient to diluent will vary from 200 parts diluent to 1 part active ingredient, to 3 parts diluent to 1 part active ingredient.

When it is desired to prepare granules as the dosage form, then these may be prepared by intimately combining the active ingredient with a pharmaceutically suitable diluent, as for example, mannitol, sorbitol, starch, lactose or sucrose or mixtures of these, and then granulating the mixture by passing through a screen of from. No. 8 to N 20 mesh size. A granulating solution such as 1 percent gurn arable, 1 percent gum tragacanth, or 2 percent gelatin solution, may be used. After drying the granulation mass the granules are screened for uniform size and filled into containers of suitable volume for dispensing. Granules are administered in teaspoonsful or tablespoonsful doses, in a unit concentration of from 1 mg. to 75 mg. of active ingredient.

When the rectal route of administration is desired for these preparations then suppositories are prepared by mixing the active ingredient with a pharmaceutically suitable suppository base, as for example, cocoa butter or polyoxyethylene glycol, which are known in the trade as Carbowaxes. The unit weight of the suppository dose form is from 1 gm. to 3 gm. with a preferred weight of 2 gm. each. The concentration of active ingredient in each suppository may range from 1 mg. to '75 mg.

The following examples illustrate the subject compounds of the present invention.

Example 1 A mixture of 25 gm. of N-morpholine-be ta-ethyl hydrazine hydrochloride and 250 gm. of lactose is moistened with a 1 percent gelatin solution. The moistened mass is passed through a No. 60 mesh sieve and air dried. The dried powder is mixed with 5 gm. of magnesium stearate and the whole compressed into inch tablets, utilizing the conventional punch and die, so that each tablet contains 25 mg. of the active ingredient, N-morpholine-beta-ethyl hydrazine hydrochloride.

The ratio of diluent to active ingredient may range from equal parts of diluent and active ingredient, to parts diluent to each part of active ingredient. The range in the ratio of diluent to lubricant is from 50 parts diluent to each part lubricant, to 100 parts diluent for each part lubricant. The range in concentration of N-morpholinebeta-ethyl hydrazine hydrochloride may vary from 1 mg. to 75 mg, per tablet, although from 10 mg. to mg. of active ingredient, per tablet, is a preferred range.

In place of the lactose utilized above, there may be substituted mannitol, starch, sucrose, sorbitol and dextrose in equal parts, by weight, for the amount of lactose specified, and in place of the 1 percent gelatin solution used as a granulating agent, there may be substituted in equal parts, by weight, a percent alcohol-water solution or a 1 percent gum arabic solution or a 1 percent gum tragacanth solution. It should be noted that the amount of granulating solution is not a fixed quantity, but a sufiicient quantity to properly moisten the mass so that it will granulate upon being passed through an appropriate mesh size sieve by a process which is well known to those versed in the art of tablet manufacture.

Example 2 in place of the N-morpholine-beta-ethyl hydrazine hydrochloride described in Example 1, above, there may be substituted in equimolecular amounts, N-morpholinebeta-ethyl hydrazine hydrobromide, N-morpholine-betaethyl hydrazine sulfate, N-morpholine-beta-ethyl hydrazine citrate, N-morpholine-beta-ethyl hydrazine tartrate, N-morpholine-beta-ethyl hydrazine succinate, N-rnorpho line-beta-ethyl hydrazine maleate and N-morpholine-betaethyl hydrazine mandelate; the remainder of the steps being the same.

Example 3 In a glass flask containing 100 gm. of cottonseed oil, is dissolved 10 gm. of N-morpholine-beta-ethyl hydrazine with the aid of gentle heat. The cooled solution is filled into soft gelatin capsules so that each capsule contains 10 mg. of N-morpholine-beta-ethyl hydrazine per unit dose.

In place of the cottonseed oil used as a solvent, there may be substituted, in equal weight, any bland vegetable oil, as for example, peanut oil, olive oil, safilower oil and soya bean oil, or an inert pharm aceutically acceptable liquid organic solvent, such as polyoxyethylene glycol, which is known in the trade as Carbowax, glycerin or propylene glycol. The usual ratio of solvent to active ingredient in preparing the liquid capsules is 10 parts solvent for each part of active ingredient, although a range of from equal parts solvent to active ingredient and 50 parts solvent to active ingredient, may be used.

Solid capsules of N-morpholine-betaethyl hydrazine may be prepared by mixing 30 gm. of N-morpholinebeta-ethyl hydrazine with 250 gm. of an inert excipient, as for example, kaolin, and to this is added 50 gm., by Weight, of lactose. The mixture is filled into hard gelatin capsules so that each capsule contains 10 mg. of N- morpholine-beta-ethyl hydrazine per unit dose.

Capsules of pharmaceutically acceptable salts of N- morpholine-beta-ethyl hydrazine may be prepared by fillmg into hard gelatin capsules, the dried granulation obtained as a result of the granulating steps of Examples 1 and 2, above. Capsules of these pharmaceutically aceptable salts of N-morpholine-beta-ethyl hydrazine may also be obtained by filling into hard gelatin capsules a mixture of equal parts of the said pharmaceutically acceptable salts of N-morpholineeta-ethyl hydrazine and a diluent selected from the group consisting of mannitol, starch, sucrose, sorbitol and dextrose.

Example 4 Suppositories may be prepared by mixing the active ingredient, as for example, N-morpholine-beta-ethyl hydrazine and its pharmaceutically acceptable salts, with a suitable carrier, as for example, cocoa butter or the solid carbowaxes (polyoxyethylene glycol) and shaping the resultant mass into suitable suppositories which range in weight from 1 gm. to 3 gm. with a preferred Weight of 2 gm. per suppository. The range in concentration of active ingredient per suppository may be from 1 mg. to mg. per suppository, with 25 mg. an optimal concentration per unit dose. In preparing the suppositories, either the cold extrusion process or a hot pour molding process may be utilized.

Example 5 Granules may be prepared by mixing 25 gm. of active ingredient, N-morpholine-beta-ethyl hydrazine with. 3 kilograms of lactose and 2 kilograms of mannitol. After thorough mixing, the mixture is moistened with a solution of 1 percent gelatin and passed through a No. 8 mesh sieve, and the granules dried. Should it be desired to flavor and color the granules, then pharmaceutically acceptable flavoring and colouring may be added.

The concentration of active ingredient to the diluent will depend upon the unit dosage desired. Thus, the above formulation will permit the administration of an average dose of 25 mg. in 1 teaspoonful (5 gm.) of granules. Should larger quantities, as for example, tablespoonful (15 gm.) dosage be desired, then appropriate adjustment in the ratio of active ingredient to carrier is made. Similarly, when smaller unit dosages, as for example, one-half teaspoonful are desired, a decrease in the ratio of carrier is made.

By utilizing identical procedure and equal amounts by Weight for the N-morpholine-beta-ethyl hydrazine described above, then the pharmaceutically acceptable salts of N-morpholine-beta-ethyl hydrazine may be utilized to prepare granules for administration.

Example 6 When it is desired to utilize N-morpholine-beta-ethyl hydrazine or its pharmaceutically acceptable salts in therapy, wherein the monamine oxydase system is involved, then these compounds may be administered in the form of a tablet, capsule, granule or suppository, in a daily dosage range of from 1 to 75 mg. per day, which is administered in divided doses. For initial treatment, the preferred dosage is 30 mg. to 50 mg, per day, which is administered in divided unit dosages of 10 mg. each. This dosage may be increased or lowered, depending upon the individual patient needs and physiologic status. Thus, the dibilitated geriatric patient, who is chronically ill, will require less of the drug than will the average adult presenting acute symptomatology present for a short period of time. Similarly, the child will require less than the adult, as would the patient presenting the less severe symptomatology in contrast to the more seriously ill patient.

For maintenance therapy, a daily dosage of from 1 to 26 mg. may be utilized, depending upon the degree of response of the individual patient.

The initial physiologic response will be observed within 3 or 4 days, with improvement and relief of symptoms generally noted within 1 to 2 weeks, for the majority of the patients.

It is not desired to be limited except as set forth in the following claims, the above description being by way of illustration of the invention.

What is claimed is:

1. A pharmaceutical composition in unit dosage form comprising a compatible pharmaceutical carrier and from 1 through mg. of N-morpholine-beta-ethyl hydrazine.

2. A pharmaceutical composition in unit dosage form comprising a compatible pharmaceutical carrier and from 1 through 75 mg. of N-morpholine-beta-ethyl hydrazine hydrochloride.

3.A pharmaceutical composition in unit dosage form comprising a compatible pharmaceutical carrier and from 1 through 75 mg. of N-morpholine-beta-ethyl hydrazine hydrobromide.

4. The method of treating depressive states which comprises the steps of administering a pharmaceutical composition comprising a compound selected from the group consisting of N-morpholine-beta-ethyl hydrazine and its pharmaceutically acceptable acid addition salts, and a compatible pharmaceutical carrier.

5. The method of treating depressive states, which comprises the step of administering in unit dosage form a pharmaceutical composition comprising a pharmaceutical carrier and from 1 through 75 mg. of a compound selected from the group consisting of N-morpholine-betaethyl hydrazine and its pharmaceutically acceptable acid addition salts.

6. The method of treating depressive states, which comprises the step of administering in unit dosage form a pharmaceutical composition comprising a pharmaceutical carrier and from 1 through 75 mg. of N-morpholinebeta-ethyl hydrazine.

7. The method of treating depressive states, which comprises the step of administering in unit dosage form a pharmaceutical composition comprising a pharmaceutical carrier and from 1 through 75 mg. of N-morpholinebeta-ethyl hydrazine hydrochloride.

8. The method of treating depressive states, which comprises the step of administering in unit dosage form a pharmaceutical composition comprising a pharmaceutical carrier and from 1 through 75 mg. of N-morpholinebeta-ethyl hydrazine hydrobromide References Cited in the file of this patent UNITED STATES PATENTS 2,830,050 Biel Apr. 8, 1958 2,937,118 Haxthausen May 17, 1960 2,953,494 Cook Sept. 20, 1960 2,955,108 Omietanski Oct. 4, 1960 2,957,873 Rudner Oct. 25, 1960 2,970,145 De Benneville Jan. 31, 1961 

1. A PHARMACEUTICAL COMPOSITION IN UNIT DOSAGE FORM COMPRISING A COMPATIBLE PHARMACEUTICAL CARRIER AND FROM 1 THROUGH 75 MG. OF N-MORPHOLINE-BETA-ETHYL HYDRAZINE. 